Herpes viruses inflict a wide range of diseases against humans and animals. For instance, herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), are responsible for cold sores and genital lesions, respectively; varicella zoster virus (VZV) causes chicken pox and shingles; and the human cytomegalovirus (HCMV) is a leading cause of opportunistic infections in immunosuppressed individuals.
Over the past two decades, a class of compounds known as the purine and pyrimidine nucleoside analogs has received the most attention by investigators in the search for new therapeutic agents for treatment of herpes virus infections. As a result, several nucleoside analogs have been developed as antiviral agents. The most successful to date is acyclovir which is the agent of choice for treating genital HSV infections. Another nucleoside analog, ganciclovir, has been used with some success in treating HCMV infections.
Nevertheless, in spite of some significant advances, the need for effective, safe therapeutic agents for treating herpes viral infections continues to exist. For a review of current therapeutic agents in this area, see R. E. Boeheme et al., Annual Reports in Medicinal Chemistry, 1995, 30, 139.
Azetidin-2-one derivatives have been reported in the literature as having variety of biological activities; mainly antibacterial, anti-inflammatory, anti-degenerative, etc. However, azetidin-2-one derivatives have not been reported to be antiviral agents against herpes viruses.
The following references disclose azetidin-2-ones having biological activity:
S. K. Shah et al., European patent application 0,199,630, Oct. 29, 1986, PA1 S. K. Shah et al., European patent application 0,377,549, Oct. 18, 1989, PA1 P. L. Durette and M. Maccoss, U.S. Pat. No. 5,100,880, Mar. 31, 1992, PA1 P. L. Durette and M. Maccoss, U.S. Pat. No. 5,104,862, Apr. 14, 1992, PA1 W. K. Hagmann et al., Bioorg. Med. Chem. Lett. 1992, 2, 681, PA1 W. K. Hagmann et al., J. Med. Chem. 1993, 36, 771, PA1 J. B. Doherty et al., U.S. Pat. No. 5,229,381, issued Jul. 20, 1993, PA1 S. K. Shah et al., Bioorg. Med. Chem. Lett. 1993, 3, 2295, PA1 G. Crawley, PCT patent WO 95/02579, published Jan. 26, 1995, PA1 P. E. Finke et al., J. Med.Chem. 1995, 38, 2449, and K. Kobayashi et al., Japanese patent application 07242624, published Sep. 19, 1995; Chem. Abstr. 1996, 124, 29520. PA1 R.sub.1 is C.sub.1-6 alkyl optionally substituted with NHC(O)--R.sub.8 or C(O)--R.sub.8 wherein R.sub.8 is a C.sub.1-6 alkyl, O--C.sub.1-6 alkyl, NH--C.sub.1-6 alkyl, (C.sub.0-4 alkyl)aryl or (C.sub.0-4 alkyl)Het, wherein Het represents a five or six-membered, monovalent heterocyclic ring containing a heteroatom selected from the group consisting of N, O, or S; PA1 R.sub.1 is an amino acid analog or dipeptide analog of the formula: ##STR4## PA1 A is C.sub.6-10 aryl, Het or CH--R.sub.3 wherein R.sub.3 is C.sub.1-6 alkyl or (C.sub.0-4 alkyl)aryl; and PA1 Z is H, C.sub.1-6 alkyl, or an acyl of formula C(O)-R.sub.8 wherein R.sub.8 is as defined above; PA1 R.sub.4 is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy; and PA1 R.sub.5 is lower alkyl, lower cycloalkyl, (CH.sub.2).sub.m --C(O)OR.sub.6 wherein m is the integer 1 or 2 and R.sub.6 is lower alkyl or phenyl(lower alkyl); PA1 phenyl, phenyl monosubstituted, disubstituted or trisubstituted with a substituent selected independently from the group consisting of: PA1 lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy and amino; phenyl(lower alkyl), phenyl(lower alkyl) monosubstituted or disubstituted on the phenyl portion thereof with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkylamino, di(lower alkyl)amino, lower acylamino, di(lower alkyl)aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl)thio, (trifluoromethyl)sulfinyl, (trifluoromethyl)sulfonyl and C(O)OR.sub.7 wherein R.sub.7 is lower alkyl or phenyl(lower alkyl); PA1 Het or Het(lower alkyl) wherein Het represents an unsubstituted, monosubstituted or disubstituted five or six membered, monovalent heterocyclic ring containing one or two heteroatoms selected from the group consisting of N, O or S, wherein each substituent is selected independently from the group consisting of lower alkyl, lower alkoxy, halo and hydroxy; PA1 5-(benzo[1,3]dioxolyl) methyl, (1(R)-1-naphthalenyl)ethyl, 2-benzothiazolyl or 2-thiazolo[4,5-b]pyridinyl; or PA1 R.sub.4 and R.sub.5 together with the nitrogen atom to which they are attached form a piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, 1-(3,4-dihydro-1H-isoquinolinyl) or 2-(3,4-dihydro-1H-isoquinolinyl) or a pyrrolidino ring optionally substituted with phenyl or C(O)OCH.sub.2 -phenyl, said phenyl ring optionally mono- or di-substituted with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkylamino, di(lower alkyl)amino, lower acylamino, di(lower alkyl)aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl)thio, (trifluoromethyl)sulfinyl, (trifluoromethyl)sulfonyl and C(O)OR.sub.7 wherein R.sub.7 is lower alkyl or phenyl(lower alkyl); or a therapeutically acceptable acid addition salt thereof. PA1 (C.sub.0-4 alkyl)phenyl wherein said phenyl ring is optionally substituted with halo, C.sub.1-6 alkyl, or NH-R.sub.9, wherein R.sub.9 is: PA1 or said nitrogen atom of said Het is substituted with R.sub.9, wherein R.sub.9 is: PA1 R.sub.1 is an amino acid analog or dipeptide analog of formula: ##STR5## PA1 A is phenyl or CH--R.sub.3 wherein R.sub.3 is C.sub.1-6 alkyl or (C.sub.0-4 alkyl)phenyl; and PA1 Z is C(O)--R.sub.8 wherein R.sub.8 is C.sub.1-6 alkyl, C.sub.1-6 alkoxy or phenyl; PA1 R.sub.4 is hydrogen or C.sub.1-3 alkyl; and PA1 R.sub.5 is phenyl optionally substituted with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy; phenyl(lower alkyl) optionally mono- or di-substituted on the phenyl portion thereof with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl, and C(O)OR.sub.7 wherein R.sub.7 is lower alkyl or (lower alkyl)phenyl; PA1 Het(lower alkyl) wherein Het represents a five or six-membered, monovalent heterocyclic ring containing a heteroatom selected from the group consisting of N, O, or S, said ring being optionally substituted with lower alkyl or lower alkoxy; PA1 or R.sub.4 and R.sub.5 together with the nitrogen atom to which they are attached form a pyrrolidino optionally substituted with C(O)O-benzyl or phenyl said phenyl ring optionally mono- or di-substituted with halo, nitro, cyano or trifluoromethyl; or a therapeutically acceptable acid addition salt thereof. PA1 phenyl, benzyl or phenylethyl wherein said phenyl ring is optionally substituted with chloro or methoxy; PA1 Het, Het-methyl or Het-ethyl, wherein Het is 2-, 3-, or 4-pyridinyl optionally substituted on the nitrogen by methyl or C(O)--R.sub.10 wherein R.sub.10 is CH.sub.2 -t-Bu or phenyl; or PA1 R.sub.1 is an amino acid analog or dipeptide analog of formula: ##STR6## PA1 A is phenyl or CH-t-Bu; and PA1 Z is C(O)--R.sub.8 wherein R.sub.8 is CH.sub.2 -t-Bu or 0-t-Bu; PA1 R.sub.4 is hydrogen or lower alkyl; and PA1 R.sub.5 is phenyl optionally substituted with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy; (C.sub.1-2 alkyl)phenyl optionally mono- or di-substituted on the phenyl portion thereof with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl, and C(O)OR.sub.7 wherein R.sub.7 is lower alkyl or (lower alkyl)phenyl; or PA1 R.sub.1 is phenyl, 4-chloro-phenyl, benzyl, phenylethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, CH.sub.2 --(S)CH(CH.sub.2 CH.sub.2 SO.sub.2 Me)--NH--Tbg--Boc, CH.sub.2 --(S)CH(CH.sub.2 CHMe.sub.2)--NH--Tbg--C(O)CH.sub.2 -t-Bu; PA1 R.sub.4 is H or Me; PA1 R.sub.12 is phenyl, benzyloxyethyl or Het; and PA1 R.sub.13 is hydrogen, methyl, ethyl, propyl or hydroxymethyl. PA1 A) The compound of formula 1 wherein Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.5 are as defined hereinabove and R.sub.4 is hydrogen can be prepared by the following processes: ##STR8## PA1 B) The compound of formula 1 wherein Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.5 are as defined hereinabove and R.sub.4 is not hydrogen can be prepared by the following process: ##STR9##